Representation of BQL values in concentration data [Bioanalytics]

As per the new Bioanalytical Method validation guidelines, "Study samples with concentrations listed below the LLOQ should be reported as below the LLOQ (BQL). Study samples with concentrations above the ULOQ should be diluted and re-analyzed, or the standard curve should be extended and revalidated."

This means, whether we have to replace BQL values with "zero" or can we keep as it is in the BE analysis without replacing those values with zero?

We have a situation that, one of our study is passing the BE with BQL values (without replacing those values with zero), but failed to attain the BE without BQL values(with replacing those values with zero).

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Best Regards,
GM

ElMaestro★★★

Denmark,
2019-02-21 06:58

@ GMPosting: # 19953Views: 433

Representation of BQL values in concentration data

» As per the new Bioanalytical Method validation guidelines, "Study samples with concentrations listed below the LLOQ should be reported as below the LLOQ (BQL). Study samples with concentrations above the ULOQ should be diluted and re-analyzed, or the standard curve should be extended and revalidated."» » This means, whether we have to replace BQL values with "zero" or can we keep as it is in the BE analysis without replacing those values with zero?

Those values are not measured as zero, they are BLLOQ or BQL or BLQ or whatever code you assign to them. However, it is a commonly accepted principle that when you do NCA on the series, you consider BLQ to be zero for the purpose of derivation of AUC. This works without problems generally, with a few exceptions; for example, there is no universal agreement on how to handle a BLQ between quantifiable concentrations after tmax when you do "linear up, log down". But I assure you there are very strong personal opinions

Your processes around sampling and reporting PK-data and doing NCA should be in an SOP, in my opinion.

» We have a situation that, one of our study is passing the BE with BQL values (without replacing those values with zero), but failed to attain the BE without BQL values(with replacing those values with zero).
Sounds like you are in a good position. But check what the software actually does with BLQs - at the end of the day this is what determines if the proof of BE is rigorous and scientific.

“(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures.” New York Times (ed.), June 9, 2018.

GM★

India,
2019-02-21 08:06

@ ElMaestroPosting: # 19954Views: 429

Representation of BQL values in concentration data

»This means, whether we have to replace BQL values with "zero" or can we keep as it is in the BE analysis without replacing those values with zero?» » Those values are not measured as zero, they are BLLOQ or BQL or BLQ or whatever code you assign to them. However, it is a commonly accepted principle that when you do NCA on the series, you consider BLQ to be zero for the purpose of derivation of AUC. This works without problems generally, with a few exceptions; for example, there is no universal agreement on how to handle a BLQ between quantifiable concentrations after tmax when you do "linear up, log down". But I assure you there are very strong personal opinions »
Yes. I agree with you. For calculation of AUC, we should consider numeric value other wise calculation will not happen with character values.

So, if we consider measured(BQL) values as it is for the calculation of AUC, are there any comments come from regulatory?

» Your processes around sampling and reporting PK-data and doing NCA should be in an SOP, in my opinion. »
We don't have any SOP and protocol also states that, follow Bioanalytical guidance.

» » We have a situation that, one of our study is passing the BE with BQL values (without replacing those values with zero), but failed to attain the BE without BQL values(with replacing those values with zero).» Sounds like you are in a good position. But check what the software actually does with BLQs - at the end of the day this is what determines if the proof of BE is rigorous and scientific.

If we keep measured values(BQL as it is) in input data, software will consider those values for the derivation. B'coz we are not providing any cutoff value for BLQ in the input data.

Representation of BQL values in concentration data

» »This means, whether we have to replace BQL values with "zero" or can we keep as it is in the BE analysis without replacing those values with zero?

You list them as BQL's (or similar), not as zeros. The true bottleneck is how the software handles it.

» So, if we consider measured(BQL) values as it is for the calculation of AUC, are there any comments come from regulatory?

Depends on how the software handles the BQL's and if regulators agree with the way it does. They don't often re-calculate the NCA in Europe, but often do so in the US.

» We don't have any SOP and protocol also states that, follow Bioanalytical guidance.

Then how do you now if you want to do lin up, log down or lin up, lin down? Even if you use default settings with commercial software I'd always recommend you to have in your SOP that this is your active choice. Having it in a protocol may achieve the same in practice, but the contents of the protocol can be said not to be part of your QMS.

» If we keep measured values(BQL as it is) in input data, software will consider those values for the derivation. B'coz we are not providing any cutoff value for BLQ in the input data.

It is very vague to me what you are saying. What does the software actually do behind the scenes, and do you agree with what it does? If so, then there's no issue really, am I right?

“(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures.” New York Times (ed.), June 9, 2018.